DESCRIPTION (Investigator's Abstract): Considerable evidence suggests that oxidative modifications to LDL are important in atherogenesis. LDL modified by in vitro oxidative stress is known to be taken up by cultured macrophages which transform into "foam cells" similar to those observed in early atherosclerotic lesions. In this investigation, the principal investigator will study the role(s) of vitamin E (tocopherol) and vitamin C (ascorbate) in modulating; (a) the oxidation of lipoproteins; (b) lipoprotein lipid composition and; (b) the catabolism of LDL by cultured macrophages. Ascorbate is a water-soluble plasma antioxidant and tocopherol is carried in the hydrophobic domain of lipoproteins. A major goal is to perform in vitro quantitative kinetic analyses of lipoprotein oxidation testing the hypothesis that ascorbate can regenerate tocopherol from the tocopheroxly radical in lipoproteins and thereby enhance the ability of tocopherol to protect against lipid peroxidation. The experimental design for these kinetic experiments requires lipoproteins with and without tocopherol. By varying the ratio of ascorbate to tocopherol, the investigators will determine if a critical level of ascorbate is required for interaction with the tocopheroxyl radical. By studying both high density lipoprotein (HDL) and LDL, the investigators will also shed light on why these lipoproteins differ in their susceptibility to oxidative damage. For these experiments, lipoproteins will be isolated from rats fed diets either deficient or supplemented with tocopherol. A second major goal will be to determine if dietary vitamin E deficiency provides sufficient in vivo oxidative stress to convert native LDL into oxidatively modified LDL capable of high affinity uptake by cultured macrophages. The influence of additional in vitro oxidative stress will also be evaluated in these macrophage uptake experiments. A third goal will be to determine if in vivo vitamin E deficiency alter the lipid composition of lipoproteins, especially the lysolecithin and plasmalogen content. Vitamin E deficiency is known to cause major alteration in the enzymes responsible for lysolecithin production. Lysolecithin is a potent chemotactic factor for macrophages and may, therefore, play a role in foam cell formation. Plasmalogens may function as natural antioxidants in lipoproteins but this hypothesis has not been critically tested.